Project Summary: Women with endometriosis may experience debilitating pelvic pain and infertility, reduced quality of life and incur significant health care costs. Endometriosis requires a surgical diagnosis, which results in an average delay of seven years to obtain a diagnosis. Once a woman is diagnosed, there is scant data on optimal treatment options and short- and long-term prognosis. Endometriosis is a heterogeneous disease not only in disease presentation but also in symptom presentation. Understanding and quantifying this heterogeneity is a crucial step to discover non-invasive diagnostic tools and to advance personalized, precision treatment options - a scientific gap addressed herein. Our proposal addresses identifying endometriosis- specific inflammatory, hormonal and miRNA (transcriptomic) plasma markers and inflammatory and transcriptomic profiles of the ectopic endometrium (endometrial lesions). We will quantify the heterogeneity in these plasma and tissue markers across: (1) symptom presentation at endometriosis diagnosis including pain sensitization, (2) surgically visualized endometriosis subtypes, and (3) participant characteristics including reproductive and gynecologic history and co-morbidities. Through the collaboration of global leading endometriosis research centers (MSU, Harvard, Oxford, Eunice Kennedy Shriver NICHD), and multidisciplinary molecular and physiology partners, we will address the hypotheses that 1) the combination of inflammatory, hormonal, and transcriptional plasma markers can be used to differentiate women with and without endometriosis; and 2) differences in the hormonal, inflammatory and transcriptional plasma and ectopic endometrial markers can be further refined by assessing the heterogeneity in disease and symptom presentation and participant characteristics. We further hypothesize that this heterogeneity will inform treatment response and prognosis. Our combined data and samples were collected by standard operating procedures, established by our World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (WERF-EPHect). Together they total nearly 2000 women with and without endometriosis and with well-annotated phenotypic data and blood samples. Among women with endometriosis, we have more than 300 existing well-annotated ectopic endometrial samples. Relevance: The discovery of informative subtypes of endometriosis and classifications of disease that lead to precise non-invasive diagnostic tools for endometriosis and the application of personalized endometriosis treatment options have remained elusive. This has resulted in significant delays in diagnosis and potentially financial and personal costs for women with endometriosis. Leveraging our multidisciplinary team with expertise in biomarkers, endometriosis heterogeneity, and epidemiology, provides an unprecedented opportunity to advance the discovery of a non-invasive diagnostic and to advance personalized, precision treatment development.